Although there are numerous theories concerning how HIV causes depletion of CD4 lymphocytes, three appear to be the most viable. The first states that HIV causes "global immune inactivation" with the concomitant increase in activation-induced cell death of CD4 lymphocytes, leading to their eventual exhaustion. The second states that HIV retards production of new CD4 lymphocytes, leading to their eventual disappearance. The third states that HIV's pathogenic mechanism is on resting CD4 lymphocytes (non-permissive for virus replication), which come into contact with HIV-coated follicular dendritic cells or productively infected cells in lymphoid tissues and are thereby signaled, resulting in enhanced homing back to lymph nodes (LNs), after entering the blood stream, and upregulation of Fas. These cells are secondarily signaled during the homing process, which leads to induction of apoptosis in many of them. Each of these theories has unique features which allow certain predictions, and these will be explored in HIV+ subjects. Our overall hypothesis is that one of these theories will be the predominant mechanism of HIV depletion of CD4 lymphocytes, and three specific aims will address this hypothesis: (1) to quantitate the frequencies of dying CD4 lymphocytes in LN biopsies of HIV patients that are Ki67+ (i.e., are activated and are undergoing "activation-induced cell death") or are thymidine phosphorylase+ (i.e., are resting cells signaled by virus contact); (2) to quantitate the frequencies of new CD4 lymphocytes in the blood of HIV patients in comparison to patients infected with viruses (HBV, HCV) which do not lead to depletion of CD4 lymphocytes; and (3) to quantitate the frequencies of dying CD4 lymphocytes in LN biopsies of HIV patients which express markers of homing receptor signaling. These in vivo studies should clarify the relative importance of each of these mechanisms in HIV patients.